Autophagy: Protection Against T2D?

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Autophagy appeared to play a key role in preventing type 2 diabetes by protecting insulin-secreting beta cells from the accumulation of toxic amylin oligomers.

Note that the studies suggest that autophagy -- controlled disposal of damaged organelles within the cell -- boosting therapies could prove to be a novel approach for type 2 diabetes prevention.

The cellular regulatory system known as autophagy appeared to play a key role in preventing type 2 diabetes by protecting insulin-secreting beta cells from the accumulation of toxic amylin oligomers, researchers reported.

Findings from three independent research teams, published online in the Journal of Clinical Investigation, suggested autophagy boosting therapies could prove to be a novel approach for type 2 diabetes prevention.

The studies provide new insight into how beta cells are normally protected against amylin (IAPP) toxic oligomers, wrote Dhananjay Gupta, PhD, and Jack L. Leahy, MD, of the University of Vermont in Burlington in an accompanying editorial.

"IAPP is a 37-amino acid protein co-expressed and secreted by pancreatic [beta cells] along with insulin," wrote Peter Butler, MD, from the University of California Los Angeles, and colleagues. "While the extracellular islet amyloid is relatively inert, intracellular membrane-permeant toxic oligomers of IAPP that form within [beta cells in type 2 diabetes] are thought to induce [beta-cell dysfunction and apoptosis]."

In contrast to the human form of IAPP (h-IAPP), which forms toxic membrane-permeant oligomers, the rodent form of IAPP (r-IAPP) is nonamyloidogenic and nontoxic due to proline substitutions. Transgenic expression of h-IAPP in [beta cells] of rodents may lead to development of diabetes as a consequence of [beta-cell] apoptosis and formation of intracellular IAPP oligomers comparable to those found in humans with type 2 diabetes.

In earlier in vitro studies, the authors reported that enhancement of autophagy was protective while attenuated lysosomal degradation rendered beta cells more vulnerable to h-IAPP-induced apoptosis.

In the current study, the researchers determined that beta-cell IAPP content is regulated by autophagy through p62-dependent lysosomal degradation.

"Induction of high levels of human IAPP in mouse [beta cells] resulted in accumulation of this amyloidogenic protein as relatively inert fibrils with cytosolic p62-positive inclusions, which temporarily averts formation of toxic oligomers," they wrote.

Mice hemizygous for transgenic expression of human IAPP did not develop diabetes. But the loss of beta cell-specific autophagy in the mice induced diabetes as a result of the accumulation of toxic human IAPP oligomers and loss of beta-cell mass, the researchers noted.

In a separate study, Yoshio Fujitani, PhD, of Juntendo University, Tokyo, and colleagues, examined the pathogenic role of human-IAPP and its relation to autophagy in h-IAPP-knock-in mice.

In animals fed a standard diet, h-IAPP had no toxic effects on beta-cell function. However, h-IAPP-knock-in mice did not exhibit a high-fat diet-induced compensatory increase in beta-cell mass, which was due to limited beta-cell proliferation and enhanced beta-cell apoptosis, the researchers wrote.

Expression of h-IAPP in mice with a beta-cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions.

"Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of h-IAPP and enhance [beta-cell] dysfunction and progression of type 2 diabetes," the researchers noted.

Autophagy Enhancers

In the third paper, Myung-Shik Lee, MD, PhD, of the Sungkyunkwan University School of Medicine in Seoul, and colleagues, studied transgenic mice with beta cell-specific expression of h-IAPP to evaluate the contribution of autophagy in type 2 diabetes-associated accumulation of h-IAPP.

In mice with beta-cell-specific expression of h-IAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing h-IAPP alone or lacking autophagy alone. Lack of autophagy in h-IAPP-expressing animals also resulted in h-IAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of beta cells.

"Expression of h-IAPP in purified monkey islet cells or a murine [beta cell] line resulted in pro-h-IAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mouse-IAPP or nonfibrillar mutant h-IAPP," the researchers wrote. "In autophagy-deficient cells, accumulation of pro-h-IAPP dimers increased markedly, and pro-h-IAPP trimers were detected in the detergent-insoluble fraction."

Enhancement of autophagy also improved the metabolic profile of h-IAPP-expressing mice fed a high-fat diet.

Gupta and Leahy noted that all three research teams generated human IAPP-expressing mice with a beta-cell-specific deficiency of the autophagy indicator ATG7, and all three found that autophagy-dependent packaging of monomeric or unprocessed IAPP dimers or trimers into p62-associated vacuoles allowed autophagosomes to dispose of these molecules, keeping them nontoxic.

Each team also showed the activity of this detoxification system to be increased when a high-fat diet was fed to the mice with hyperexpression of h-IAPP.

The studies build on previous work and the findings were not surprising, Gupta and Leahy wrote, adding that it is still is not clear "how and when during the course of type 2 diabetes development this autophagy-dependent detoxification system might be overcome, allowing toxic IAPP oligomers to form."

"There are many additional mechanisms that have been proposed for [beta-cell] dysfunction and death in type 2 diabetes, including ER stress, oxidative stress, and autoimmune damage, all of which have been linked to IAPP toxicity," they wrote. "While it is tempting to try and connect the dots through a single, unified mechanism, all of these proposed pathways of [beta-cell] dysfunction have been recapitulated and extensively studied in rodent models of diabetogenic systems, such as high-fat feeding and partial pancreatectomy, or through genetic modification."

Given the absence of rodent IAPP oligomerization, these mechanisms of reduced beta-cell function clearly do not require IAPP activation, they noted.

Still, findings from the papers have important potential implications for the study of new target therapies for the prevention of type 2 diabetes and for understanding the pathogenesis of T2D and other diseases, they said.

"Patients with type 2 diabetes have an increased risk of Alzheimer's disease, suggesting a common pathogenesis," they wrote. "Disordered neuronal autophagy has been described in Alzheimer's, such that a widespread alteration in the clearance of amyloidogenic proteins may explain the association between these two diseases, and it is an important issue for further investigation."

They concluded that acceptance of the hypothesis that IAPP oligomer formation and subsequent plaque development are a major cause of type 2 diabetes will require a better understanding of when this mechanism is activated and what modulates its destructive potential.

"These current studies may have provided an important clue by shifting the focus away from the biology of how IAPP oligomers cause [beta cell] destruction to probing for defects within the protective system against the formation of toxic IAPP oligomers," they wrote.

The study by Butler's group was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the NIH, the Larry L. Hillblom Foundation, and the Esther B. O'Keeffe Foundation.

Butler and co-authors disclosed no relevant relationships with industry.

The study by Fujitani's group was supported by grants from the Ministry of Education, Sports and Culture of Japan, Japan Diabetes Foundation, Daiichi-Sankyo Foundation of Life Science, the UBE Foundation, and the Institute for Environmental and Gender-Specific Medicine, Juntendo University.

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